Colored transmission electron micrograph (TEM) of a section through the bacteria Neisseria. Image: Pasieka/Science Photo Library. |
Life
inside the human body sometimes looks like life on the high seas in the 1600s,
when pirates hijacked foreign vessels in search of precious metals.
For Neisseria bacteria, which can cause
gonorrhea and meningitis, the booty is not gold or silver but plain old iron.
Until
recently, scientists did not understand how these bacteria snatch iron from
healthy human cells, where a protein called transferrin binds the metal in a
molecular bear-hug. However, a new study led by scientists at the National
Institutes of Health in collaboration with biophysicist James Gumbart at the
U.S. Department of Energy’s Argonne National Laboratory has demonstrated the
likely process by which the bacteria steal the biologically valuable metal.
Within the
pathogenic Neisseria bacteria, the
iron transport system consists of a two-part membrane protein complex that
binds human transferrin. At the molecular level, the primary membrane protein
involved—called TbpA—resembles a narrow barrel, woven from a strand of amino
acids, the building blocks of all proteins. When not in the process of
transport, the barrel of TbpA is blocked by a separate region of the same
protein that forms a kind of “plug” to prevent other molecules from
freely entering or leaving the bacterium, said Gumbart.
“Normally,
this protein looks something like a wine bottle with a cork inside of it,”
he said. “When an iron-containing transferrin comes along though, TbpA is
opened by another protein inside the bacterium, which pulls on the cork and brings
the iron in.”
To gain a
better understanding of how the theft unfolds in real time, Gumbart developed
computational models that highlight electrostatic changes in TbpA during
opening. Initially, the interior of the barrel is negatively charged, creating
a “sucking” effect that extracts the iron from transferrin. As TbpA
opens, however, the electrostatic potential gradient in the barrel becomes more
positive, thereby expelling the iron into the bacterial cell.
The
long-term goal of the research, according to Gumbart, is to use this discovery
to drive the development of a new class of antibiotics that would prevent the
heists from taking place.
“Without
iron, these bacteria don’t have a hope of surviving,” he said.
“Proteins
like TbpA make highly attractive targets because they are unique to specific
classes of bacteria,” Gumbart added.
“Now
that we have a better idea of how this process works, we should be able to use
the knowledge we’ve gained to combat these diseases.”
The result
of the study appears online in Nature.
